Prolyl-4-hydroxylase 2 enhances hypoxia-induced glioblastoma cell death by regulating the gene expression of hypoxia-inducible factor-?.

ABSTRACT: Oxygen deprivation (hypoxia) is a common feature of solid tumors in advanced stages. The primary cellular transcriptional responses to hypoxia are mainly mediated by the transcription factor hypoxia-inducible factor (HIF). HIF consists of an oxygen-labile ?-subunit (HIF-1?, -2?) and a stable ?-subunit (ARNT). Prolyl-4-hydroxylase 2 (PHD2) is known as an important mediator of the oxygen-dependent degradation of HIF-? subunits. As HIF-? subunits are not confirmed to be the only substrates of PHD2, it is unknown whether PHD2 regulates HIF-1? and HIF-2? by interacting with other intracellular molecules. In this study, we found that in the glioblastoma cells, PHD2 maintains the gene expression of HIF-1? in dependence of nuclear factor ?B and suppresses the gene expression of HIF-2? through HIF-1?. The PHD2-mediated degradation of HIF-1? and HIF-2? seems less important. Furthermore, PHD2 enhances hypoxia-induced glioblastoma cell death by modulating the expression of the HIF target genes glucose transporter 1, vascular endothelial growth factor-A and Bcl-2 binding protein 3. Our findings show that PHD2 inhibits the adaptation of glioblastoma cells to hypoxia by regulating the HIF-? subunits in a non-canonical way. Modulation of PHD2 activity might be considered as a new way to inhibit glioblastoma progression.

SUBMITTER: Sun W 

PROVIDER: S-EPMC4123088 | biostudies-other | 2014 Jul

REPOSITORIES: biostudies-other